HIESP @ Broad‎ > ‎


Defining the full allelic spectrum of variation in IBD genes

Crohn’s disease (CD) and ulcerative colitis (UC) are debilitating, inflammatory diseases of the gastrointestinal tract, collectively known as the inflammatory bowel diseases (IBD).  Among complex diseases, genetics has been particularly successful in the identification of genes for IBD, with the latest efforts in genome-wide association studies (GWAS) defining confirmed association to 163 gene loci. Specific validated functional variants have have highlighted the significance of intracellular response to microbes and regulation of adaptive immunity in the pathogenesis of IBD.  For the vast majority of these associations, the specific implicated gene and causal functional variants have not been identified, dramatically limiting the near-term insights into pathogenesis and the longer-term ability to convert these associations into actionable therapeutic hypotheses.  The swift progress of GWAS in many disease areas has exposed this same limitation – it is becoming clear that the primary challenge for human genetics is no longer discovering genetic associations, it is in the articulation of how the identified genes and corresponding alleles exert their influence on the biology of health and disease.

With support from the Helmsley Charitable Trust, we have launched a transformative program of exome sequencing in IBD for which we continue to engage collaborative partners. The overarching aim of the program is to define the full allelic spectrum of protein-altering variation in genes associated to IBD, assess their role in both CD and UC risk, clinical course and response to therapy, and to determine whether loss-of-function variants confer risk or protection in each IBD gene in order to articulate the most opportune therapeutic targets.  Recent technical innovations in DNA sequencing and analysis enable exome sequencing to take place at an unprecedented low cost and high accuracy and have facilitated the launch of this program, which aims to evaluate at least 20,000 exomes over the course of the next 2-3 years.